Possible New Reaction Mechanisms of Dideoxynucleosides as Anti-Aids Drugs

Abstract

Evidence is presented that a major class of drugs, the dideoxynucleosides (ddNs) and nucleoside/nucleotide analogues, may inhibit the symptoms of acquired immunodeficiency syndrome (AIDS) by initiation of inactivation at the ribonucleotide reductase (RNR) enzyme stage and/or inactivation of reverse transcriptase enzyme or at a stage more initial than that of the currently accepted DNA chain termination hypothesis. For example, it has been previously shown that ribonucleotide diphosphate reductase (RDPR) and ribonucleotide triphosphate reductase (RTPR) are inactivated with 2′-chloro-2 ‘-deoxyuridine 5′-diphosphate-([3′-3H]ClUDP) and triphosphate ([3′-3H]ClUTP) by reaction with an intermediate furanone, Scheme 2. RDPR has also been inactivated by 2‘-azido-2‘-deoxyuridine 5‘-diphosphate (N3UDP). Furthermore, addition of hydroxyurea to RNR can inhibit DNA synthesis which results in a rapid depletion of limiting deoxynucleotide triphosphate (dNTP) pools. There are similar perturbations of dNTP pools upon interaction of human RNR with 3‘-azido-2‘,3 ‘-dideoxythymidine (AZT), in human cell studies involving AZT/HIV and in adenosine/coformycin experiments in relation to inherited immunodeficiency, Table 1. Also, the herein proposed reduction mechanisms of nucleotides by RNR ( e.g., a single electron transfer from the nucleotide base to the phenol moiety of the tyrosyl radical of RNR via a pathway involving the thiyl radical of a cysteine residue) can also account for the chemistry of some antiretroviral drugs, the ddNs. Analyses are presented that the RNR reductions of regular unsubstituted nucleotides may occur predominantly via initial 2’ C-H abstraction instead of the originally proposed 3’ C-H abstraction mechanism. Also, it is noted that the fate of the phenol moiety of the tyrosyl unit in some RNR reactions with 2‘-halo-2‘-deoxynucleotides is not clear. The proposed reaction mechanisms may provide guidance for the development of potentially effective anti-AIDS drugs.